Among white adults, otosclerosis is the single most common cause of hearing impairment. The disease is caused by abnormal bone homeostasis of the otic capsule, which usually results in a conductive hearing loss due to fixation of the stapes footplate, although sensorineural hearing loss also may occur. The etiology of otosclerosis is unknown, and both genetic and environmental factors have been implicated. Although the genetics of otosclerosis are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. Using two large families showing this type of Mendelian inheritance pattern, we have localized two otosclerosis-causing genes, OTSCI and OTSC2. We also have shown that at least one additional locus, OTSC3, exists. Continuing on this initial body of work, we propose to: 1) Clone the OTSCI and OTSC2 genes; 2) Identify novel otosclerosis loci by linkage analysis; 3) Identify novel otosclerosis loci by linkage and linkage disequilibrium analyses in families from Greece; 4) Identify novel otosclerosis loci by non-parametric linkage analysis using affected sib pairs.